SFTPA2 – SFTPA2-related Interstitial Lung Disease 2

Idiopathic pulmonary fibrosis (IPF), categorized under interstitial lung disease 2 (MONDO:0800029), is an adult-onset, progressive fibrotic lung disorder. Heterozygous mutations in the surfactant protein A2 gene (SFTPA2) impair SP-A2 folding and secretion, leading to endoplasmic reticulum (ER) stress and alveolar epithelial cell apoptosis, consistent with autosomal dominant inheritance.

Early genetic studies mapped familial IPF with lung adenocarcinoma to chromosome 10q, identifying rare missense SFTPA2 variants co-segregating in two independent pedigrees (n = 2 families)[PMID:19100526]. Affected individuals carried invariant-residue substitutions in the carbohydrate recognition domain (e.g., c.667C>A (p.Gln223Lys), c.271G>C (p.Ala91Pro)) that were retained within the ER and not secreted, implicating a dominant-negative or haploinsufficient mechanism.

In a Chinese IPF kindred, whole-exome sequencing revealed a novel SFTPA2 variant c.619A>T (p.Asn207Tyr) segregating with all affected relatives (n = 3)[PMID:32602668]. Functional assays in A549 cells showed reduced SP-A2 secretion, activation of the unfolded protein response (BiP upregulation, XBP1 splicing), and increased apoptosis, mirroring the pathogenic consequences of previously described variants.

Sequencing of IPF cohorts further detected rare SFTPA2 missense changes (e.g., c.532G>A (p.Val178Met)) in sporadic cases, supporting the recurrence of pathogenic alleles across unrelated probands[PMID:25553246]. Together, at least six unrelated probands harbor heterozygous SFTPA2 mutations consistent with autosomal dominant risk and with segregation in multiple families.

Mechanistic studies demonstrate that mutant SP-A2 (G231V, F198S) remains misfolded in the ER, forms NP-40–insoluble aggregates, and undergoes ER-associated degradation, triggering ER stress and epithelial apoptosis[PMID:20466729; PMID:23056344]. Chemical chaperone 4-phenylbutyric acid (4-PBA) and EGCG mitigate aggregation and enhance secretion, confirming the pathogenic mechanism and suggesting potential therapeutic strategies[PMID:30293573; PMID:31546020].

No studies have refuted the SP-A2–ILD 2 association. The collective data fulfill ClinGen criteria for a Strong gene–disease relationship, with multiple pedigrees, segregation, and consistent functional concordance.

Key Take-home: Heterozygous SFTPA2 missense mutations cause autosomal dominant interstitial lung disease 2 via impaired SP-A2 secretion, ER stress, and alveolar epithelial apoptosis, warranting inclusion in diagnostic and therapeutic planning.

References

• American journal of human genetics • 2009 • Genetic defects in surfactant protein A2 are associated with pulmonary fibrosis and lung cancer. PMID:19100526
• Molecular genetics & genomic medicine • 2020 • Identification and functional characterization of a novel surfactant protein A2 mutation (p.N207Y) in a Chinese family with idiopathic pulmonary fibrosis. PMID:32602668
• PloS one • 2012 • Human surfactant protein A2 gene mutations impair dimmer/trimer assembly leading to deficiency in protein sialylation and secretion. PMID:23056344
• The Journal of biological chemistry • 2010 • Surfactant protein A2 mutations associated with pulmonary fibrosis lead to protein instability and endoplasmic reticulum stress. PMID:20466729
• Biochimica et biophysica acta. Molecular basis of disease • 2018 • Chemical chaperone 4-phenylbutyric acid alleviates the aggregation of human familial pulmonary fibrosis-related mutant SP-A2 protein in part through effects on GRP78. PMID:30293573
• The international journal of biochemistry & cell biology • 2019 • Epigallocatechin-3-gallate (EGCG) inhibits aggregation of pulmonary fibrosis associated mutant surfactant protein A2 via a proteasomal degradation pathway. PMID:31546020

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